The present invention is directed to neuroprotective (antiischemic and excitatory aminoacid receptor blocking) 5-(1-hydroxy-2-piperidinopropyl)-2(1H,3H) -indolone analogs, defined by the formula (I), (II) and (III) below; pharmaceutically acceptable salts thereof; a method of using these compounds in the treatment of stroke, traumatic brain injury or CNS degenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease and Parkinson's disease; and to certain intermediates therefor.
Ifenprodil is a racemic, so-called dl-erythro compound having the relative stereochemical formula ##STR1## which is marketed as a hypotensive agent, a utility shared by a number of close analogs; Carron et al., U.S. Pat. No. 3,509,164; Carron et al., Drug Res., v. 21, pp. 1992-1999 (1971). Ifenprodil has also been shown to possess antiischemic and excitatory aminoacid receptor blocking activity; Gotti et al., J. Pharm. Exp. Therap., v. 247, pp. 1211-21 (1988); Carter et al., loc. cit., pp. 1222-32 (1988). See also published European patent application 322,361 and French Patent 2546166. A goal, substantially met by the present invention, has been to find compounds possessing such neuroprotective effect in good measure, while at the same time having lowered or no significant hypotensive effect.
Certain structurally related 1-phenyl-3-(4-aryl -4-acyloxypiperidino)-1-propanols have also been reported to be useful as analgesics, U.S. Pat. No. 3,294,804; and 1-[4-(amino- and hydroxy-alkyl)phenyl]-2-(4-hydroxy -4-tolylpiperazino)-1-alkanols and alkanones have been reported to possess analgesic, antihypertensive, psychotropic or antiinflammatory activity, Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A), 53-59,675 (CA 89:146938w; Derwent Abs. 48671A) and 76,118,772 (CA 86:189738m).
More recently, in published European Patent Application No. 351,282, compounds which include those of the formula ##STR2## wherein R.sup.a and R.sup.b are each independently hydrogen or (C.sub.1 -C.sub.4)alkyl, R.sup.c is benzyl, phenoxy, benzyloxy or phenoxymethyl, and Z.sup.a is CH.sub.2, C(CH.sub.3).sub.2 or CH.sub.2 CH.sub.2, have been reported as having neuroprotective type activity.
Also, amino ketone and amino alcohol derivatives of benzoxazolinone and their adrenergic and antihypertensive properties are described in the European Journal of Medicinal Chemistry, 25, 361-368, (1990), C.A. 113:191213f.
The nomenclature used herein is generally that of Rigaudy et al., IUPAC Nomenclature of Organic Chemistry, 1979 Edition, Pergammon Press, New York. 2(1H,3H)-Indolones are alternatively named as oxindoles.